In 1568, Gilbert was married off to Mary Cavendish, daughter of his new stepmother, Bess of Hardwick, and who has inherited much of her formidable mother's strength of character. When Bess and her husband fell out, Gilbert took the side of his wife and his mother-in-law against his own father. However, when the old earl died in 1590, Gilbert refused Bess the widow's portion she felt was her due, and consequently they fell out. He appears to have been a highly quarrelsome individual, feuding with not only his stepmother but his brother and other family members, his tenants, and even Elizabeth I herself. He was overshadowed by his formidable wife: Francis Bacon remarked that she was undoubtedly "greater than he".

He was elected knight of the shire (MP) for Derbyshire in 1572. He was summoned to the House of Lords as Baron Talbot in 1589 and became 7th Earl of Shrewsbury on his father's death in 1590.[3]

In 1592, he was created a Knight of the Garter, but feuded with his former friend John Stanhope when John's brother got the post of Earl Marshal of England, which Gilbert had assumed would be his. Gilbert's stepbrother Charles Cavendish challenged Stanhope to a duel for his sake, which was not fought. Elizabeth I was displeased and took Stanhope's side.[4] After this Gilbert challenged his own brother Edward to a duel over a lease, but Edward refused to fight him. Gilbert accused his brother of planning to poison him, but lost his case against him.

He became a patron of the arts, as was his daughter Alethea, who became Countess of Arundel by her marriage to Thomas Howard in 1606. Talbot's second daughter, Elizabeth, married Henry Grey, 8th Earl of Kent. The eldest, Mary, married William Herbert, 3rd Earl of Pembroke. As well as bringing up their three daughters, Gilbert and Mary Talbot spent a good deal of time with their orphaned niece, Arbella Stuart. The downfall of Arbella, who as the closest relative of King James I of England had greatly offended him by marrying without his consent, had serious consequences for Gilbert and Mary: Mary, who had aided the marriage, went to the Tower of London as a result, and Gilbert lost his seat on the Privy Council.

In the absence of a male heir, he was succeeded in the earldom of Shrewsbury by his younger brother, Edward. However, some of the extensive estates passed then (or after Edward's death) to his daughters.